Although Abundant in Tumor Tissue, Mast Cells Have No Effect on Immunological Micro-milieu or Growth of HPV-Induced or Transplanted Tumors

Abstract

High numbers of mast cells populate the stroma of many types of neoplasms, including human papilloma virus-induced benign and malignant tumors in man and mouse. Equipped with numerous pattern recognition receptors and capable of executing important pro-inflammatory responses, mast cells are considered innate sentinels that significantly impact tumor biology. Mast cells were reported to promote human papilloma virus (HPV)-induced epithelial hyperproliferation and neo-angiogenesis in an HPV-driven mouse model of skin cancer. We analyzed HPV-induced epithelial hyperplasia and squamous cell carcinoma formation, as well as growth of tumors inoculated into the dermis, in mice lacking skin mast cells. Unexpectedly, the absence of mast cells had no effect on HPV-induced epithelial growth or angiogenesis, on growth kinetics of inoculated tumors, or on the immunological tumor micro-milieu. Thus, the conspicuous recruitment of mast cells into tumor tissues cannot necessarily be equated with important mast cell functions in tumor growth.

Unimpaired Responses to Vaccination With Protein Antigen Plus Adjuvant in Mice With Kit-Independent Mast Cell Deficiency

“…Mcpt5-Cre R26 DTA/DTA mice featured virtually complete absence of CTMCs in peritoneal cavity and skin without alteration of other hematopoietic cell subsets in peritoneum, skin, spleen, bone marrow, or blood as determined by flow cytometry and histology (Figure S1 in Supplementary Material). We had earlier shown highly efficient depletion of skin MCs on formalin-fixed, Giemsa-stained sections (47). As mucosal MCs of the intestinal tract can be metachromatically stained using special fixation procedures like Carnoy fixation but not after formalin fixation, we now performed additional Giemsa staining of Carnoy-fixed skin to exclude the presence of skin MC populations that fail to stain with conventional protocols (Figure S1 in Supplementary Material) and confirmed near complete absence of MCs in the skin of Mcpt5-Cre R26 DTA/DTA mice.…”

Mast cells—Good guys with a bad image?

“…As MCs can infiltrate the surrounding stroma of certain tumors, [69][70][71] many studies performed in human and mice focused on the role of MCs in tumor immunology. Whereas some studies revealed no effect of MCs on tumor progression, [72][73][74] others reported a positive role of MCs and pointed out MCs as responsible for tumor growth inhibition in mice, or related the presence of MCs to a good prognosis for the patient. 75,76,[76][77][78] A positive influence of MCs can rely on their ability of the release of antitumorigenic molecules such as tumor necrosis factorα, IL-9, or IL-6.…”

Mast cells drive IgE-mediated disease but might be bystanders in many other inflammatory and neoplastic conditions

“…However, when the experiment was repeated in the KITindependent Mcpt5-Cre R26 DTA model of MC deficiency, neoplastic growth and tumor angiogenesis were not impaired compared with that seen in control mice, despite the absence of MCs. 58 Likewise, HPV-induced epidermal neoplasia was unaffected by selective inactivation of the Vegfa gene in MCs. 58 Also, in the Cpa3 Cre/1 model of MC deficiency, absence of MCs had no effect on epidermal tumor growth, which was in this case induced chemically.…”

“…48 Mcpt5-Cre bacterial artificial chromosome transgenic mice express Cre in CTMCs but not in MMCs, allowing for efficient selective gene inactivation in CTMCs. 53,[57][58][59] In addition, a small fraction of NK cells expressed Cre. 59 The line was crossed to R26 DTA mice, 60 in which Cre-mediated excision of a stop results in suicidal expression of diphtheria toxin.…”

“…25 The list of seemingly MC-dependent immune and disease processes inferred from observations in KIT mutant strains that did not reproduce in KIT-independent models has grown long. 48,[51][52][53]55,57,58,[64][65][66][67][68][69][70] These discrepancies must reflect a fundamental problem inherent to either one or the other type of model. Overwhelming evidence has accumulated indicating that KIT mutants have important problems as models of MC deficiency, even in cases in which the original experiments in the KIT mutant strains had been controlled by reconstitution with in vitro-differentiated MCs.…”